WO2011084507A1 - Treatment of nasal and sinus disorders - Google Patents
Treatment of nasal and sinus disorders Download PDFInfo
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- WO2011084507A1 WO2011084507A1 PCT/US2010/060558 US2010060558W WO2011084507A1 WO 2011084507 A1 WO2011084507 A1 WO 2011084507A1 US 2010060558 W US2010060558 W US 2010060558W WO 2011084507 A1 WO2011084507 A1 WO 2011084507A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the external nose begins at the forehead and passes inferiorly to the lower lip.
- the upper half of the nose is narrow and composed of bone, the lower half of the nose is cartilage and projects forward and widens laterally to form the nostrils.
- the nasal bones are in the midline, lateral to them are the nasal process of the maxillary bone, then the lacrimal bone, and then on the side of the eye, the ethmoid bone. These bony plates are separated by small gaps called sutures which are relatively minor barriers for drugs to pass. The bony plates also have perforations for blood vessels and nerves which also serve as soft tissue conduits for drug delivery. Thin cartilage plates give the nasal alae their shape. These cartilages have gaps between them that drugs can diffuse through if applied topically or when delivered by inj ction.
- the nasal cavity is divided into two symmetrical halves by the nasal septum, a central partition of bone and cartilage; each side opens at the face via the nostrils and connects with the mouth at the nasopharynx.
- the nasal vestibule is the initial airspace, and its interior surface is covered with skin. After the nasal vestibule air passes into the nasal cavity which is largely covered with typical respiratory epithelium, except superiorly where specialized olfactory epithelium is present.
- the nasal mucosa is continuous with the mucosa of the sinuses at the sinus openings (ostia).
- the major functions of the nose are to warm, humidify and filter inspired air.
- specialized olfactory mucosa sample the inspired air for its smell.
- the passages are narrow, normally only 1-3 mm wide, and this narrows structure enables the nose to carry out its main functions.
- inspiration the air comes into close contact with the nasal mucosa and particles such as dust and bacteria are trapped in the mucous. Additionally, the inhaled air is warmed and moistened as it passes over the mucosa; and to perform these functions there is a high blood supply in the nasal epithelium.
- the lateral wall of the nasal cavity includes three folded structures called turbinates: the superior, the median and the inferior. The turbinates channel airflow and can swell to decrease airflow.
- the nasal respiratory epithelium is generally described as a pseudo-stratified ciliated columnar epithelium.
- the four main types of cells seen in the respiratory epithelium are ciliated columnar cells, non-ciliated columnar cells, goblet cells and basal cells.
- the proportions of the different cell types vary in different regions of the nasal cavity. In the lower turbinate area, about 15-20% of the total numbers of cells are ciliated and 60-70% is non-ciliated epithelial cells.
- the role of the ciliated cells is to transport mucus towards the pharynx.
- the numbers of ciliated cells increase towards the nasopharynx with a corresponding decrease in non-ciliated cells.
- goblet cells which contain numerous secretory granules filled with mucin, h conjunction with the nasal glands; the goblet cells produce secretions, which form the mucus layer.
- Rhinitis is one of the most common disorders in medicine. Approximately 60 million Americans suffer from rhinitis each year. The symptoms of rhinitis are 1) rhinorrhea, post-nasal drip and runny nose; 2) congestion; and 3) sneezing and itching in allergic rhinitis.
- the congestion of rhinitis can lead to edema and polyps. In addition it can cause obstruction of the eustachian tubes, causing serous otitis media. Moreover, it can obstruct the opening of the sinuses, leading to bacterial sinusitis.
- rhinitis therapy The annual cost for rhinitis therapy is approximately $10B in the United States alone.
- These therapies include nasal sprays (Rhinocort®, Flonase®, Beconase®, Astelin®, Atrovent®), antihistamines (Allegra®, Claritin®, Zyrtec®, Singulair®) as well as many other prescription and over the counter medications.
- Typical therapy for rhinitis requires the use of more than one drug to have a therapeutic effect. Some of these are used several times a day. However, the benefits are often unpredictable while the drugs can cause bothersome side effects. As allergic diseases are increasing in industrialized countries their related disorders and complications are also increasing. For example, deaths from asthma are actually higher now than 20 years ago. In addition all major pharmaceutical companies have at least one major drug product in this category, and many of these have lost or about to lose their patent protection. In summary, patients, physicians, and the pharmaceutical industry are all looking for safe and effective therapies that are predictable and cause less patient discomfort. Botulinum neurotoxin (BoNT)
- BoNT Botulinum toxin
- botulinum toxin to treat rhinitis was introduced with U.S. 5,766,605 which taught the intranasal use of botulinum toxin to treat rhinorrhea in a condition called vasomotor rhinitis.
- This method was validated by preclinical and clinical studies incorporated here in their entirety by reference (Shaari et al, Otolaryngol Head Neck Surg. 1995 Apr; 1 12(4):566-71.; Rohrbach et al, ORL J Otorhinolaryngol Relat Spec. 2001 Nov-Dec; 63(6):382-4; Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2003 Nov;17(l l):643-5).
- BoNT has been applied by injections into the mucosa of the nasal cavity or by packing the nose with gauze soaked in BoNT solution. Injections are undesirable due to pain, bleeding and risk of contamination. Gauze soaked in BoNT can leak out of the nose and the actual amount delivered is unpredictable.
- BoNT botulinum toxin
- a further object of the invention to provide a method of treating a nasal or sinus condition, or symptom thereof, comprising administering a therapeutically effective amount of botulinum toxin (BoNT) by jet or pressure injection to a selected site of a mammal suffering from a nasal or sinus condition, or symptom thereof, wherein the nasal or sinus condition, or symptom thereof, is treated.
- BoNT botulinum toxin
- the BoNT is administered by needle injection, microneedle injection, jet or pressure injection, or topical application.
- the selected site is selected from the group consisting of the nasal skin overlying the nasal cartilates, nasal bones, maxillary bones, lacrimal bones, ethmoid bone, or frontal bones; the nasal tip; the external nares; the nasal alae; the palpated boy margin of the pyriform aperture; the lacrimal sac or duct; under the lip; the gingival mucosa; the sphnopalatine foramen; and the infraorbital foramen.
- the BoNT is delivered by needle injection through nasal, ethmoid, frontal maxillary, or palatine bones.
- the BoNT is delivered by jet or pressure injection across the anterior walls of the maxillary sinus.
- the nasal or sinus condition is selected from the group consisting of rhinitis, infectious rhinitis, allergic rhinitis, sinusitis, asthma, COPD, migraine headache, impaired cerebral blood flow, sleep breathing disorders, and ocular disorders.
- the symptom is selected from the group consisting of nasal congestion, sneezing, rhinorrhea, postnasal drip, nasal or sinus pain, headache, coughing, wheezing, itching, redness, thickened nasal mucosa, and nasal polyp.
- the dose of BoNT is from about 0.1 to about 100,000 units. In further embodiments, the dose of BoNT is from about 1 to about 100 units.
- the BoNT is combined with a skin permeability enhancing agent. In some embodiments, the BoNT is combined with a gel. In further embodiments, the viscosity of the gel increases after administration. In further embodiments, the gel is a temperature sensitive poloxamer.
- the BoNT is applied with a penetration enhancing agent.
- the penetration enhancing agent is selected from the group consisting of allergen, histamine, and electrical stimulation.
- a Clostridia neurotoxin (CnT) other than BoNT is used in place of BoNT.
- another CnT is used in combination with BoNT.
- Figures 1A, IB, 1C, and ID depict various aspects of the nasal anatomy.
- Figure ID identifies the glabella 1, nasion 2, rhinion 3, alar sidewall 4, alar facial groove or junction 5, supratip 6, tip-defining points 7, and the philtrum 8.
- Figures 2 A, 2B, and 2C depicts various views of the nasal anatomy.
- Figure 2 A depicts the lateral view of the sagittal plane.
- Figure 2B depicts the frontal view of the frontal plane.
- Figure 2C depicts the inferior view of the axial plane.
- Reference number 21 identifies the pyriform aperture.
- Reference number 22 identifies the septum.
- Reference number 23 identifies the inferior turbinate.
- Figure 3 depicts a lateral view of the nasal bones and cartilage. Specifically identified are the nasal bone 31, the nasion (nasofrontal suture line) 32, internasal suture line 33, nasomaxillary suture line 34, ascending process of maxilla 35, rhinion, or osseocartilaginous junction 36, upper lateral cartilage 37, caudal edge of upper lateral cartilage 38, anterior septal angle 39, lower lateral cartilage lateral crus 40, medial crural footplate 41, intermediate crus 42, sesamoid cartilage 43, and the pyriform aperture 44.
- nasal bone 31 the nasal bone 31
- the nasion (nasofrontal suture line) 32 internasal suture line 33
- nasomaxillary suture line 34 ascending process of maxilla 35, rhinion, or osseocartilaginous junction 36
- upper lateral cartilage 37 caudal edge of upper lateral cartilage
- Figure 5 depicts underlying bones of the intranasal anatomy.
- Figure 6 depicts the lacrimal system. Specifically identified are the punctum 61, canaliculus 62, common canaliculus 63, middle turbinate 64, valve of Hasner 65, inferior turbinate 66, lacrimal sac 67, and the nasolacrimal duct 68.
- the lacrimal system drains tears from the surface of the eye. Tears enter punctum 61 at the medial aspect of the eyelids and drain into a lacrimal sac 67, then downward to drain into nasal cavity below inferior turbinate 66.
- Figure 7 depicts a coronal section of the nasal cavity.
- the superior concha 71 Specifically identified are the superior concha 71, sinus drainage cavities 72, middle concha 73, inferior concha 74, the anterior cranial fossa 75, the orbit 76, the superior meatus 77, middle meatus 78, and maxillary bore 79.
- Figure 8 depicts skin areas of the nose (indicated by cross hatching) where topical diffusible BoNT can be applied.
- Figure 8A is a lateral view
- Figure 8B is a frontal view
- Figure 8C is an inferior view
- Figure 8D is a lateral view.
- the shaded area of Figure 8D indicates underlying skin in the intranasal area.
- Figure 9 depicts exemplary needle approaches to the nasal cavity.
- the darker areas of the needle bore designate that part of the needle that is outside skin.
- the lighter areas of the needle bore are inside or have passed through tissue.
- Injection can be made after puncturing skin from outside of the nasal cavity, or the needle tip can be advanced directly to the nasal mucosa.
- Figure 9 A shows a lateral view of an injection in the nasion that passes through skin and between or through the nasal bones.
- Figure 9B is a frontal view of an injection between nasal cartilages. Slight changes in angulation can reach either side of the septum and either lateral nasal wall.
- Figure 9C shows an inferior view of a needle entering and passing through nasal alae to reach inferior turbinate.
- Needle position 91 shows an injection in the nasion that passes through skin and between or through nasal bones.
- Needle position 92 shows an injection between nasal cartilages. Slight changes in angulation can reach either side of the septum and either lateral nasal wall.
- Needle position 93 shows the needle entering and passing through nasal alae to reach the inferior turbinate.
- Needle position 94 shows the needle entering mucosa under the lip and passing across nasal airspace to enter the inferior turbinate.
- Need position 95 shows the needle entering the skin of the cheek and passing the pyriform edge to reach the inferior turbinate.
- Figure 10 depicts exemplary transdermal nasal pressure injection.
- Figure 10A depicts a lateral view of transdermal pressure injection to the inferior turbinate.
- Figure 10B shows a frontal view of transdermal pressure injection to the inferior turbinate.
- Figure IOC shows an inferior view of transdermal pressure injection to the inferior turbinate.
- Figure 10D shows a lateral view of injection to the nasal septum.
- Figure 10E shows a frontal view of injection to the nasal septum,
- Figure 10F shows an inferior view of an injection to the nasal septum.
- Figure 11 depicts exemplary deliveries by intranasal spray.
- Intranasal spray can coat interior mucosa with droplets or particles containing BoNT.
- Figure 11 A shows a lateral view of delivery by intranasal spray.
- Figure 1 IB shows a frontal view of delivery by intranasal spray.
- Figure 1 1 C shows an inferior view of delivery by intranasal spray.
- Figure 12 depicts exemplary delivery by intranasal pressure injection.
- Figure 12A shows a lateral view of delivery by intranasal pressure injection.
- Figure 12B shows a frontal view of delivery by intranasal pressure injection.
- Figure 12C shows an inferior view of delivery by intranasal pressure injection.
- Botulinum toxin refers to botulinum serotypes A, B, C, D, E, F, G. BoNT also encompasses all modified or substituted versions of these toxins that have the same blocking effect on snare proteins. These include any substitution or modification of at least 1 amino acid of a naturally produced toxin or novel toxins made with recombinant techniques. Also included are toxins with removal or substitution of the binding domain and/or translocation domain. Also included are methods of drug delivery including liposomes, protein transduction domains, cationic proteins, acidic solutions and numerous other methods known in the art. These variations are discussed in WO 2004/1076634 and US 7,491,799, which are incorporated by reference in their entirety.
- BoNT drugs that are those using botulinum toxin A manufactured by Allergan Inc., Irvine, CA (Botox®). Other toxins have known biological equivalence ratios to Botox. Dysport from Ipsen LTD, Bath, England has l/3 rd the bio equivalence per unit of Botox®. Myobloc (Botulinum toxin type B), Solstice Neuroscience, Malvern, PA has l/40 th the bioequivalence of Botox®.
- Clostridia neurotoxin (CnT) refers to a neurotoxin derived from a species of Clostridia, including, without limitation, C. botulinum (including BoNT as described above), C. butyricum, C. beratti, and C. tetani.
- Microneedle injection refers to extremely thin and short solid or hollow needles.
- Microneedles are solid or hollow needle structures that are much thinner than hypodermic needles. Suitably they are 1 to 100 micron in thickness andThey can penetrate the mucosa or skin with little or no pain.
- the BoNT can be coated on the surface of these needles such that they are physically passed through mucosa and then diffuse off the surface of the needle into tissue.
- the botulinum toxin can be topically applied to mucosa, and microneedles can then be used to make micropunctures through which the BoNT can diffuse.
- the microneedles can be hollow and serve as conduits through which BoNT can be delivered (US 6,558,361 , incorporated herein by reference in its entirety).
- the conduit of a microneedle is very thin so that volumes of .1 to 10 ml require many microneedles (from 1 to 1,000,000) and/or delivery over extended periods of time (1 second to 1 week).
- the hollow microneedles may be attached to a reservoir of drug solution (e.g., US 3,964,482).
- the flow of drug may be increased by applying pressure (about .001 to about 100 pounds per square inch) (e.g., US20090030365) or an electrical field (e.g., US 6,256,533).
- Needle injection refers to hypodermic needles.
- small gauge needles e.g. gauge 27-36.
- Pressure or Jet injection refers to a method of injection in which pressure injectors propel drug via brief pulses of highly pressurized gas.
- pressure injectors are J-tip needle-free syringes, National Medical Products Inc, Irvine, CA, and SyriJet, Mizzy, Cherry Hill, NJ (.2ml).
- US 5,049,125 discloses a device for pressure injection and is hereby incorporated in its entirety.
- US 5,630,796, hereby incorporated by reference in its entirety describes a needleless syringe that delivers pharmaceutical particles entrained in supersonic gas flow from Mach 1 to Mach 8.
- Optimum particle densities for transdermal delivery range between about 0.1 and 25 g/cm.3, and optimal velocities range between 100 and 3000 m/sec.
- Yamada (Anesth Prog 51 :56-61 2004) described using pressure syringes to inject small drugs like epinephrine into nasal mucosa.
- Diffusable formulation means BoNT that can diffuse across mucosa or skin and subcutaneous tissues. These may be BoNT suspended in liposomes or coated by transduction proteins.
- WO 2006/094263 describes such formulations and is hereby incorporated by reference in its entirety.
- Allergic rhinitis (hayfever), non-allergic rhinitis, infectious rhinitis, sinusitis, asthma, COPD (bronchitis and emphysema), migraine headache, impaired cerebral blood flow, headache, sleep breathing disorders, and ocular disorders can each be treated by the application of BoNT to the nose or sinus, or to the nerves innervating these structures.
- BoNT can unexpectedly be applied to areas surrounding these structures, for example, from about 1 to about 100 mm away, and still have a therapeutic effect. Doses of BoNT can, for example, range from about 0.1 to about 1000 units, or from about 1 to about 100 units.
- BoNT causes changes in airway reflexes that improve sleep disordered breathing, asthma, and COPD. BoNT also causes changes in vasomotor reflexes and tone that improve cerebral circulation and tone.
- BoNT can be delivered transdermally to nasal and sinus mucosa by topical compositions, needle injection, microneedle injection, or by pressure injection. The BoNT can pass across skin, subcutaneous tissue, and if necessary, bone and cartilage.
- injection can be made to the hard palate, especially the nerve foramina.
- Asthma can be treated by application of BoNT to intranasal or sinus mucosa, or the nerves innervating these structures.
- the BoNT is applied to the nasal fontanels.
- BoNT Decreased cerebral circulation can be treated by intranasal and sinus application of BoNT.
- the large surface area and vascularity of the nasal and sinuses distributes BoNT to many vascular neurons.
- Retrograde transport of BoNT to central neurons distributing to other areas of the head causes relaxation of arteries with increased flow.
- Vascular headaches are decreased by the same relaxation effect.
- BoNT is administered to the sphenopalatine ganglion, where many of these vascular neurons concentrate.
- BoNT has been applied by injections into the mucosa of the nasal cavity or by packing the nose with gauze soaked in BoNT solution. Injection into mucosa with needles is undesirable due to pain, bleeding and risk of contamination. Gauze soaked in BoNT can leak out of the nose and the actual amount delivered is unpredictable. In addition, any procedure within the nose, whether needle injection or topical, would require an Ear, Nose and Throat specialist (otolaryngologist) thereby making the procedure more expensive and harder to obtain than if it could be performed by general medical practitioners. [0064]
- drugs with BoNT being one non-limiting example, can be delivered to the nasal mucosa by application outside the nasal cavity. This can be done safely with less pain and side effects than intranasal injection. Moreover, this method allows broader use and greater patient acceptance.
- Drugs delivered by this invention can be those treating nasal and sinus disorders (steroids, antihistamines, nasacrom, antibiotics).
- this invention includes drugs delivered to the nasal and sinuses intended for systemic distribution; ex insulin; and vaccines.
- the areas allowing external application are the nasal skin overlying the nasal cartilages, nasal bones, maxillary, lacrimal, ethmoid, and frontal bones.
- the lacrimal system can be used to delivery drugs to the nasal cavity as well as to the eyelids and conjunctiva.
- drugs can also be delivered transmucosally to the nasal and sinus cavities. Injection can be performed across the gingival mucosa under the upper lip. The upper margin of the gingival is almost level with the floor of the nasal cavity. More laterally, injections can be made across the gingival mucosa and the anterior wall of the maxillary sinus, particularly in the area of the infraorbital foramen.
- injection can be made into the oral mucosa of the hard palate, where the extensions of the nasopalatine nerves terminate. Injections also can be made where the nerves cross, specifically the foramina.
- the external nasal skin overlaps or is close to intranasal mucosa. Therefore, medication that can diffuse through soft tissue can be applied topically and reach the mucosa. Substances that are capable of this include liposomes and protein transduction domains, and cationic proteins, and nanoemulsions (See, e.g., US20090163412, US20070077259, US20100150994, and US20100172943, each of which is incorporated by reference in their entireties).
- the topical medication is placed on skin overlying mucosa, such as the nasal alae.
- the diffusion need only travel the thickness of the skin, about 1-2 mm. However, diffusion can travel laterally also, such that it can be placed on the nasal tip and skin around the nose. Therefore the distance of diffusion can vary from about 1 mm to about 2 cm.
- BoNT can be delivered across mucosa with jet injection, microneedles or by disrupting the mucosal barrier by concomitant application of allergens, chemicals, or energy.
- BoNT The passage of BoNT over the nasal mucosa can be facilitated by application of allergens, chemicals, osmotic pressure, or energy to open mucosal barriers.
- allergens In allergic individuals, allergens cause openings between nasal mucosa cells and allow proteins to diffuse across the mucosa. Any substance causing inflammation also opens the mucosal barrier.
- Certain chemicals are known to cause the same effect. Suitable agents include cationic polymers, bioadhesive agents, surface active agents, fatty acids, chelating agents, mucolytic agents, cyclodextrin, microsphere preparations or combinations thereof. (US 5,629,011, US 10/596,817, and US 7,696,343, each of which is hereby incorporated by reference in its entirety).
- the BoNT carrier be bioadhesive so that it sticks to the mucosa rather than leak away.
- Bioadhesive compositions are known in the art (US 7,846,478, incorporated herein by reference in its entirety).
- a 30 year old female has allergic rhinitis as reflected by post nasal drip, congestion and sneezing. She also has allergic asthma reflected by wheezing and coughing.
- a gel carrier can be placed ont eh skin of the nasal vestibule.
- BoNT dermal area that BoNT can be applied is shown in Figure 8.
- the preferable mucosa for allergic rhinitis is the most anterior part of the nasal cavity.
- Needle injection can be performed across external nasal skin in any of the cross hatched areas shown in Figure 8. Once across skin BoNT can be injected into the soft tissue and allowed to diffuse to the nasal mucosa. However, there is less need for diffusion and more efficient delivery if the needle is advanced to a mucosal target. In some embodiments, the needle can be advanced directly to the nasal mucosa. In other embodiments, the needle may then pass through the nasal mucosa and thereby enter the nasal cavity where it can be redirected to inject multiple areas.
- a 20 year old male complains of seasonal sneezing and congestion and is diagnosed with allergic rhinitis.
- His physician injects 20 units of BoNT mixed with .5 cc normal saline into the anterior tip of each inferior turbinate. Specifically the physician feels the patient's face to find the bony margin of the nasal aperture.
- a lcc syringe with a 1" 32 gauge needle is filled with 40 units of BoNT.
- the needle is inserted at or within the palpated bony margin of the pyriform aperture.
- the level of the inferior turbinate is just superior to the attachment of the nasal alae to the face.
- the needle is inserted 4mm deep and BoNT/saline mixture is injected over 1 min.
- the needle is withdrawn and the same injection is performed on the opposite side.
- the patient is then sent home.
- Follow-up appointment in 2 weeks shows that the patient's sneezing and congestion has greatly improved.
- Pressure injectors propel drug via brief pulses of highly pressurized gas.
- a large molecule such as BoNT can be propelled across skin, subcutaneous tissue, bone, fat and mucosa.
- Injection can be straight into tissue or at an angle. Injection can remain within tissue or pass into the nasal cavity.
- the injection depth can vary from .1 mm to 20 mm.
- the volume injected can vary from .01 ml to 10 ml. Pressure ranges, particle sizes and speeds are taught in the references cited above.
- the nozzle of a pressure injector can be applied at the external nares with the angle facing toward intranasal mucosa; at the pyriform aperture with the angle facing toward intranasal mucosa; over the nasal bones with injection passing through the bones; above the lacrimal sac or duct with injection passing across skin and entering these structures; Under the lip against gingival with the angle toward intra nasal mucosa; under the lip against mucosa with the angle facing directly through the anterior wall of the maxillary sinus (or directed through the foramen); and against the hard palate at the sphenopalatine foramen with the injection going toward the sphenopalatine ganglion.
- a 50 year old male has chronic rhinitis.
- a pressure injector nozzle is placed extranasallly on the nasal alae, the shaft is pointed transverse toward the pyriform bony margin, A 20 bar pressure pulse projects a .1ml solution of 10 units of BoNT into the skin and through subcutaneous tissue to end in nasal mucosa in and around the inferior turbinate. As figure 10 shows, the nozzle angle can vary.
- aerosol sprays are impractical with botulinum toxin as aerosolized liquid particles can be inhaled into the lungs.
- pressurized droplets or particles that are propelled directly from nozzle to target mucosa circumvent the problem of aerosolized medication.
- spray better characterizes this invention.
- droplets of liquid or gel, or dry particles are sprayed into the nostril. This method is a variant of topical application.
- the sprays consist of BoNT within a carrier such as a bioadhesive gel or particles (including nanoparticles).
- Spray-congealing consisting of the atomization of a dispersion of the drug in a molten carrier, is a solvent-free technique, which may be advantageous for the preparation of mucoadhesive micro particles.
- Chitosan, sodium carboxymethylcellulose and poloxamers are examples of carrier materials.
- Zhou and Donovan used putative bioadhesive polymers such as methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, carbopol 934P, chitosan glutamate and pluronic F127 for the study of mucociliary clearance with the use of rat model.
- the mucociliary clearance for these polymer gels from nasal cavity was determined by following removal of microspheres which are fluorescently labeled and incorporated in the formulation. It was found that the pluronic F127 and other polymer gel formulations have longer residence times and hence decrease mucociliary clearance.
- Another embodiment of this invention is the use of pressure injection within the nose. This is superior to needle injection as there is no mucosal puncture.
- the difference between this and nasal spray is that pressure injection is held against tissue and uses higher pressures to force medication into tissue. In some cases the pressure is used to force medication through constricted spaces such as the ostia of sinuses. In still other embodiments the pressure injector is used to inject across thin bone.
- a 40 year male complains of perennial rhinitis with significant congestion and post nasal drip.
- the patient has used topical steroids without relief.
- Examination shows swollen mucosa bilaterally and mucous rhinorrhea.
- the physician uses a pressure injector with a 6 cm nozzle.
- the injector is set to inject a .5 cc bolus containing 50 units of BoNT in normal saline.
- the physician decongests both nasal cavities with 1% neosynephrine spray.
- the nasal mucosa is sprayed with 1% lidocaine. Under direct vision the nozzle is advanced to the posterior superior nasal cavity and pressed against mucosa.
- the pulse drives the BoNT solution through the thin bone into the pterygopalatine space. Within that space the Sphenopalatine ganglion is blocked, thereby causing a nearly complete block of efferent innervation to the nose and sinuses. In two weeks the patient reports decreased nasal congestion and post nasal drip.
- the lacrimal system is illustrated in figure 6.
- the lacrimal system drains tears from the eyes through puncta at the inner aspect of eyelids. These in turn connect to the lacrimal sac, and then drain through a duct to be released into the lateral wall of the nose.
- the lacrimal system is a convenient conduit for delivering BoNT the nasal cavity.
- the lacrimal sac is a convenient spot for drug depot, large volumes or drug reservoirs that elute drug over long periods.
- BoNT can be delivered to the lacrimal system in a variety of ways. It can be dissolved in eye drops that drain into the punctum. It can be injected or pressure injected through the punctum. It can be delivered by special punctum needles as shown in middle photo. It can be injected or diffuse across skin into lacrimal sac or nasolacrimal duct.
- a 40 year old male with allergic rhinitis and allergic conjunctivitis has 10 units BoNT in .lcc normal saline pressure injected across skin into each lacrimal sac. Within 1 week his symptoms have diminished by 50% and this lasts for 4 months.
- needle injection can be performed through nasal, ethmoid, frontal, maxillary or palatine bones.
- pressure injection can be performed across the anterior walls of the maxillary sinus, particularly at the site of the infraorbital formen.
- the injection can be done across including the skin of the cheek or under the lip and across the intraoral mucosa.
- BoNT a part of this invention is the treatment of asthma and other lung diseases by application of BoNT to the head and neck, preferably the upper airway and most preferably the nasal mucosa.
- the amount of BoNT applied can be .1 to 1000 units, more preferably 1 to 100 units.
- BoNT can be applied unilaterally or bilaterally, topically or by needle or pressure injection. The methods described in this application and referenced applications can be used to deliver the toxin to nasal mucosa.
- a 20 year old male has a ten year history of asthma. He has end expiratory wheezing most days and has had to come to emergency rooms 3 times in the past year. He currently is taking inhaled steroids.
- Fifty units of BoNT in 1 cc of normal saline solution is placed on gelfoam pads that are placed in each nasal cavity. Alternatively, twenty units of BoNT could be injected into each inferior turbinate, or twenty units of BoNT could be pressure injected across the nasal wall into the Sphenopalatine ganglion. After 1 week the patient's wheezing diminishes. After 1 month he stops his inhaled steroids and notes no increased difficulty breathing.
- a 10 year old male has allergic asthma. Symptoms include wheezing and coughing. Patient has severe exacerbations every month requiring emergency room visits. His physician sprays a poloxamer gel impregnated with 10 units of BoNT into each nostril. The viscous gel is dispersed into particles and land on the surface of the medial and lateral walls. The BoNT dissolves from the particles and reaches mucosa. At a follow-up appointment 1 month later the patient reports diminished wheezing and coughing. There have been no exacerbations this month. Improvement persists for 5 months.
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Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/516,338 US20120251576A1 (en) | 2009-12-15 | 2010-12-15 | Treatment of Nasal and Sinus Disorders |
EP10842552.1A EP2512507A4 (en) | 2009-12-15 | 2010-12-15 | Treatment of nasal and sinus disorders |
CA2784552A CA2784552A1 (en) | 2009-12-15 | 2010-12-15 | Treatment of nasal and sinus disorders |
CN2010800629988A CN102781467A (en) | 2009-12-15 | 2010-12-15 | Treatment of nasal and sinus disorders |
JP2012544766A JP2013514376A (en) | 2009-12-15 | 2010-12-15 | Treatment of nasal and sinus diseases |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28651309P | 2009-12-15 | 2009-12-15 | |
US61/286,513 | 2009-12-15 |
Publications (1)
Publication Number | Publication Date |
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WO2011084507A1 true WO2011084507A1 (en) | 2011-07-14 |
Family
ID=44305710
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2010/060558 WO2011084507A1 (en) | 2009-12-15 | 2010-12-15 | Treatment of nasal and sinus disorders |
Country Status (6)
Country | Link |
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US (1) | US20120251576A1 (en) |
EP (1) | EP2512507A4 (en) |
JP (1) | JP2013514376A (en) |
CN (1) | CN102781467A (en) |
CA (1) | CA2784552A1 (en) |
WO (1) | WO2011084507A1 (en) |
Cited By (14)
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US20120251576A1 (en) * | 2009-12-15 | 2012-10-04 | Ira Sanders | Treatment of Nasal and Sinus Disorders |
US9579368B2 (en) | 2012-09-06 | 2017-02-28 | Norwegian University Of Science And Technology (Ntnu) | Treatment of headache by injection of neuroinhibitory substance to sphenopalatine ganglion or otic ganglion |
US10201594B2 (en) | 2012-10-28 | 2019-02-12 | Revance Therapeutics, Inc. | Compositions and methods for safe treatment of rhinitis |
US10960060B1 (en) | 2019-10-18 | 2021-03-30 | Penland Foundation | Treatment of cardiac arrhythmia using botulinum toxin |
US10960061B1 (en) | 2019-10-18 | 2021-03-30 | Penland Foundation | Treatment of amyotrophic lateral sclerosis using botulinum toxin |
US10967052B1 (en) | 2019-10-18 | 2021-04-06 | Penland Foundation | Treatment of dyslexia using botulinum toxin |
US10973873B1 (en) * | 2019-10-18 | 2021-04-13 | Penland Foundation | Treatment of asthma using botulinum toxin |
US10987411B1 (en) * | 2019-10-18 | 2021-04-27 | Penland Foundation | Treatment of chronic obstructive pulmonary disease using botulinum toxin |
US11090371B1 (en) | 2019-10-18 | 2021-08-17 | Penland Foundation | Treatment of cirrhosis using botulinum toxin |
US11241479B2 (en) | 2019-10-18 | 2022-02-08 | Penland Foundation | Treatment methods using botulinum toxins |
US11439694B2 (en) | 2019-10-18 | 2022-09-13 | Penland Foundation | Botulinum toxin for use in treatment of autism spectrum disorders |
US11484580B2 (en) | 2014-07-18 | 2022-11-01 | Revance Therapeutics, Inc. | Topical ocular preparation of botulinum toxin for use in ocular surface disease |
US11738071B2 (en) | 2021-07-12 | 2023-08-29 | Penland Foundation | Treatment of acute and chronic kidney disease |
US11925677B2 (en) | 2021-07-12 | 2024-03-12 | Penland Foundation | Treatment of diabetes and chronic pancreatitis using botulinum toxin |
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US9211248B2 (en) | 2004-03-03 | 2015-12-15 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
WO2020047158A1 (en) * | 2018-08-28 | 2020-03-05 | Ira Sanders | Therapeutic medications for the sphenopalatine ganglion |
CN113303876B (en) * | 2021-06-01 | 2022-09-02 | 南阳市第二人民医院 | Rotary mechanism and medical paranasal sinus suction cutter |
US20230077040A1 (en) * | 2021-08-25 | 2023-03-09 | Arthur Yajing YU | Nonsurgical methods for nasal modification including nasal tip elevation and/or elongation |
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2010
- 2010-12-15 US US13/516,338 patent/US20120251576A1/en not_active Abandoned
- 2010-12-15 CA CA2784552A patent/CA2784552A1/en not_active Abandoned
- 2010-12-15 CN CN2010800629988A patent/CN102781467A/en active Pending
- 2010-12-15 JP JP2012544766A patent/JP2013514376A/en active Pending
- 2010-12-15 WO PCT/US2010/060558 patent/WO2011084507A1/en active Application Filing
- 2010-12-15 EP EP10842552.1A patent/EP2512507A4/en not_active Withdrawn
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US20120251576A1 (en) * | 2009-12-15 | 2012-10-04 | Ira Sanders | Treatment of Nasal and Sinus Disorders |
US9579368B2 (en) | 2012-09-06 | 2017-02-28 | Norwegian University Of Science And Technology (Ntnu) | Treatment of headache by injection of neuroinhibitory substance to sphenopalatine ganglion or otic ganglion |
US10716834B2 (en) | 2012-09-06 | 2020-07-21 | Norwegian University Of Science And Technology (Ntnu) | Intervention device |
US11712464B2 (en) | 2012-09-06 | 2023-08-01 | Norwegian University Of Science And Technology (Ntnu) | Intervention device |
US10201594B2 (en) | 2012-10-28 | 2019-02-12 | Revance Therapeutics, Inc. | Compositions and methods for safe treatment of rhinitis |
US11484580B2 (en) | 2014-07-18 | 2022-11-01 | Revance Therapeutics, Inc. | Topical ocular preparation of botulinum toxin for use in ocular surface disease |
US10960060B1 (en) | 2019-10-18 | 2021-03-30 | Penland Foundation | Treatment of cardiac arrhythmia using botulinum toxin |
US10973873B1 (en) * | 2019-10-18 | 2021-04-13 | Penland Foundation | Treatment of asthma using botulinum toxin |
US10987411B1 (en) * | 2019-10-18 | 2021-04-27 | Penland Foundation | Treatment of chronic obstructive pulmonary disease using botulinum toxin |
US11090371B1 (en) | 2019-10-18 | 2021-08-17 | Penland Foundation | Treatment of cirrhosis using botulinum toxin |
US11241479B2 (en) | 2019-10-18 | 2022-02-08 | Penland Foundation | Treatment methods using botulinum toxins |
US11439694B2 (en) | 2019-10-18 | 2022-09-13 | Penland Foundation | Botulinum toxin for use in treatment of autism spectrum disorders |
US10967052B1 (en) | 2019-10-18 | 2021-04-06 | Penland Foundation | Treatment of dyslexia using botulinum toxin |
US10960061B1 (en) | 2019-10-18 | 2021-03-30 | Penland Foundation | Treatment of amyotrophic lateral sclerosis using botulinum toxin |
US11744881B2 (en) | 2019-10-18 | 2023-09-05 | Penland Foundation | Treatment of amyotrophic lateral sclerosis using botulinum toxin |
US11883473B2 (en) | 2019-10-18 | 2024-01-30 | Penland Foundation | Treatment of dyslexia using botulinum toxin |
US11738071B2 (en) | 2021-07-12 | 2023-08-29 | Penland Foundation | Treatment of acute and chronic kidney disease |
US11925677B2 (en) | 2021-07-12 | 2024-03-12 | Penland Foundation | Treatment of diabetes and chronic pancreatitis using botulinum toxin |
Also Published As
Publication number | Publication date |
---|---|
EP2512507A1 (en) | 2012-10-24 |
CA2784552A1 (en) | 2011-07-14 |
CN102781467A (en) | 2012-11-14 |
US20120251576A1 (en) | 2012-10-04 |
JP2013514376A (en) | 2013-04-25 |
EP2512507A4 (en) | 2013-04-17 |
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